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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems
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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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  • C07D515/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
  • C07D515/18—Bridged systems
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Definitions

• the present invention relates to bifunctional compounds which can bind to a ubiquitin ligase and also to a target protein, such that the target protein is placed in proximity to the ubiquitin ligase in order to induce its degradation.
• the Ubiquitin-Proteasome System is responsible for the maintenance of healthy and well- balanced proteome.
• ubiquitin units are covalently attached to the protein, forming a polyubiquitin chain, which marks the protein for degradation via the proteasome.
• Ubiquitination is central to the regulation of nearly all cellular processes and is also tightly regulated itself.
• Ubiquitin ligases facilitate ubiquitination of different proteins in vivo and contribute to precise regulation of the system. Upon recognition, the ubiquitin ligases mediate the attachment of ubiquitin moieties to the target protein, which label it for degradation by the proteasome.
• TPD target protein degradation
• Oncogenic stress such as DNA damage
• DNA damage may result in programmed cell death, the cellular response meant to prevent the oncogenic transformation.
• This mechanism depends on an interplay between pro-apoptotic and anti-apoptotic Bcl-2 proteins, and the balance of these proteins is essential for the proper functioning of the cell.
• BCL-2, BCL-xL and MCL-1 are BH3-domain-containing anti-apoptotic proteins. These proteins bind to effector Bcl-2 proteins Bak and Bax (via their BH3 domains), preventing their pro-apoptotic activity. Inhibition of BH3 domain - BH3 pocket binding interface is a well-known approach to cancer therapy (Leber B, Kale J, Andrews DW. Cancer Discov. 2018 Dec;8(12):1511-1514). High expression of induced myeloid leukaemia cell differentiation protein (MCL-1) is observed in many human cancers and is associated with resistance to cytotoxic drugs.
• MCL-1 induced myeloid leukaemia cell differentiation protein
• MCL-1dependent such as multiple myeloma, acute myeloid leukaemia, chronic myeloid leukaemia, B-cell acute lymphoblastic leukaemia, hepatocellular carcinoma and non-small cell lung cancers. This concept was confirmed in vitro and in vivo (Tron AE et al. Nat Commun. 2018 Dec 17;9(1):5341).
• MCL-1 is a driver of adaptive survival in tumor cells treated with oncogene targeted therapies, therefore MCL-1 targeting drugs are likely to overcome cancer resistance to these therapeutics.
• MCL-1 has been shown to be essential for cardiac homeostasis in adult murine models, and the absence of MCL-1 led to loss of cardiomyocytes.
• Clinical trials involving MCL-1 inhibitors are currently on clinical hold to evaluate a safety signal for cardiac toxicity (Wei AH et al. Blood Rev. 2020 Nov;44:100672).
• M is O or NH, or is absent; indicates attachment to R 18 of the linker;
• R 22 is hydrogen, halogen or an amino group
• L' is hydrogen, alkyl, benzyl, acetyl or pivaloyl
• [MCL-1 ligand moiety] is a compound of Formula (A), Formula (B) or Formula (C) wherein is a single bond or a double bond;
• R 8 is H, R 19 , or C 1 -C 6 alkyl optionally substituted with morpholine;
• R 9 is -C(O)OH, -C(O)O C 1 -C 6 alkyl; -C(O)NH 2 ; -C(O)OR 19 or -C(O)NHR 19 ,
• R 10 is -C 2-5 alkyl-O-R 13 , wherein R 13 is phenyl, naphthyl or tetraline, wherein the phenyl, naphthyl or tetraline is optionally substituted with at least one substituent selected from halogen, C 1 -C 6 alkyl and -O( C 1 -C 6 alkyl); or wherein the naphthyl is optionally substituted with -O- or -S-,
• R 11 is H, halogen or C 1 -C 6 alkyl, wherein R 20 is Me, -CH 2 -O-bromobenzaldehyde, or ; or when
• R 12 is and R 10 is -O-naphthyl substituted with -O- or -S-, then R 20 is , wherein indicates attachment to -O- or -S- of R 10 ; and wherein
• R 19 is a bond connected to R 14 of the linker;
• R 23 is -C(O)OH or -C(O)OC 1 -C 6 alkyl;
• Z 2 is N or C, wherein when Z 2 is N, then is a single bond; and when Z 2 is C, then is a double bond,
• R 24 is furan optionally substituted with at least one halogen, each R 25 is independently phenyl substituted with -OR 28 and optionally further substituted with at least one substituent selected from halogen and C 1 -C 6 alkyl;
• R 26 is -C(O)OR 19 or -C(O)NHR 19 ; and each R 28 is independently -C 1-3 alkyl-(N-alkyl piperazine) or -C 1-3 alkyl-(N-haloalkylpyrazole) and wherein each of Formula (A), Formula (B) and Formula (C) contains a single R 19 ; and wherein [linker] has the following formula R 14 -R 15 -R 16 -R 17 -R 18 wherein
• R 14 is -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyI, -C(O)-, -SO 2 - or is absent
• R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkyl-NH-, -cycloalkyl-NH- or is absent
• R 16 is -C 1-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH 2 -C(O)-, -CH 2 -C(O)-NH-, -CH 2 -C(O)O- or is absent
• R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x , (C 3 H 6 -O) x , or is absent x is 1-10 y is 2-10
• R 18 is -C 1-6 alkyl, heterocycloalkyl, or is absent wherein at least one of R 14 -R 18 is present with the proviso that: when
• R 10 is -C 3 H 6 -O-naphthyl
• R 12 is then R 9 is -C(O)OH, -C(O)OC 1 -C 6 alkyl or -C(O)NH 2 , and [ligase ligand moiety] is
• R 22 is hydrogen or an amino group. In some embodiments, R 22 is hydrogen.
• L' is hydrogen or methyl. In some embodiments, L' is hydrogen.
• [ligase ligand moiety] is:
• [ligase ligand moiety] is:
• [ligase ligand moiety] is:
• [ligase ligand moiety] is
• [ligase ligand moiety] is:
• [ligase ligand moiety] is:
• [ligase ligand moiety] is:
• [ligase ligand moiety] is
• R 14 is -C 1-6 alkyl, -SO 2 - or is absent
• R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, -C 1-6 al kyl-NH-, or is absent, wherein indicates attachment to R 14 and indicates attachment to R 16
• R 16 is -C 1-6 alkyl, -C(O)-, -C(O)-NH-, -CH 2 -C(O)-NH- or is absent
• R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x , (C 3 H 6 -O) x , or is absent x is 1-6 y is 2-6
• R 18 is -C 1-6 alkyl, piperazine, or is absent wherein at least one of R 14 -R 18 is present.
• R 18 is -C 1-6 alkyl or is absent.
• R 14 when R 14 is -SO 2 -, at least two of R 15 -R 18 are present, and at least one of R 15 - R 18 is not C 1-6 alkyl.
• R 14 is -SO 2 -;
• R 15 is -C 1-6 alkyl-NH-;
• R 16 is -C(O)-;
• R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x or is absent; and
• R 18 is -C 2-4 alkyl.
• R 15 is -C 2 alkyl-NH-; x is 1 or 2; and y is 1.
• R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, -C 1-6 alkyl-NH-, then R 14 is -C 1-6 alkyl.
• R 14 is -C 1-6 alkyl
• R 15 is piperazine, bridged piperazine, piperazine N-oxide,
• R 16 is -C(O)-, -CH 2 -C(O)-NH-, or is absent
• R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x , (C 3 H 6 -O) x , or is absent, and
• R 18 is -C 1-6 alkyl. wherein when R 16 and R 17 are absent, R 18 is -C 3.6 alkyl.
• R 14 is -C 2 alkyl; x is 1, 2 or 6; and y is 2.
• R 14 is absent, R 15 is absent, R 16 is -C(O)-NH- or is absent; R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x , (C 3 H 6 -O) x , or is absent; and R 18 is -C 1-6 alkyl.
• At least one of R 14 -R 18 is not -C 1-6 alkyl.
• x is 1, 2 or 3; y is 2; and R 18 is -C 2-6 alkyl.
• R 15 is -C 1-6 alkyl-NH-
• at least one of R 16 -R 18 is present.
• R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x or (C 3 H 6 -O) x
• at least one of R 14 -R 16 and R 18 is present, wherein at least one of R 14 and R 18 is not -C 1-6 alkyl.
• [linker] is selected from
• R 13 is
• R 8 is H, R 19 , methyl, or -CH 2 CH 2 -morpholine;
• R 9 is -C(O)OH or -C(O)NHR 19 ;
• R 10 is -C 3 H 6 O-R 13 , wherein R 13 is , tetraline, or naphthyl optionally substituted with fluorine;
• R 11 is H, Cl, F or methyl
• Z 2 is N and is a single bond. In other embodiments, Z 2 is C and is a double bond.
• R 11 is hydrogen. In other embodiments, R 11 is halogen or C 1 -C 6 alkyl. In some embodiments, R 11 is halogen.
• [MCL-1 ligand moiety] is selected from:
• the compound is selected from:
• the compound is selected from:
• the compound is selected from:
• each alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl is unsubstituted.
• each of X 1 and X 2 is independently O or S; each of Q 1 and Q 2 is independently N or CR 5 , wherein at least one of Q 1 and Q 2 is N; each of E 1 , E 2 , E 3 and E 4 is independently N or CR'; n is 0, 1 or 2; L 2 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R'", - C(O)OR”', -C(O)NH 2 , -C(O)NHR"', -C(O)NR"' 2 , -OR'", -NR'" 2 , or -S(O) 2 R'"; each R 5 is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH
• each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR'", -NR'" 2 , -NR'"C(O)R'", -NR'"C(O)OR"', -NO 2 ,
• each of X 1 and X 2 is independently or O S;
• Z 1 is O, S or NR 6 ;
• R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; each of Y 5 , Y 6 , Y 7 , and Y 8 is independently N or CR 7 , wherein at least one of Y 5 , Y 6 and Y 7 in Formula (Va) is CR 7 , and at least one of Y 5 , Y 5 and Y 8 in Formula (Vb) is CR 7 ; n is 0, 1 or 2;
• L 3 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R"", - CH 2 C(O)OR''", -C(O)OR'"', -C(O)NH 2 , -C(O)NHR”", -C(O)NR"" 2 , -OR"", -NR"" 2 , or
• each R 7 is independently hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR"", -NR"" 2 , -CH 2 NR"" 2 , -NR""C(O)R”", -NR""C(O)CH 2 NR"” 2 , -NR""C(O)CH 2 -heterocycloalkyl, -NR""C(O)CH(OH)R"", -CH 2 NR""C(O)OR”", -NR""C(O)OR”", -NR'"'SO 2 R"", -NO 2 , -CN, -C(O)R”", -C(O)OR'"',
• R 6 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroa ryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR"", -NR"" 2 , -NR""C(O)R”", -N[C(O)R””] 2 , -NR'"'C(O)OR”", -NO 2 , -CN, -C(O)R”", -C(O)OR”", -C(O)NH 2 , -C(O)NHR”", -C(O)NR”” 2 , -OR”", -OC(O)R”", -OC(O)OR”", -OC(O)NH 2 , -OC(O)NHR'"', -OC(O)NR”” 2 , -SR"", or -S(O) 2
• Z is O, S or NR 2 ;
• Y 3 is N or CR
• Y 4 is N or CR; indicates a single or double bond, wherein when each is a double bond, each of W 1 , W 2 , W 3 and W 4 is independently N or CR a , wherein at least one of W 1 , W 2 , W 3 and W 4 is N, and when each is a single bond, W 1 , W 2 , W 3 and W 4 are each CR a 2 and Y 4 is CR; n is 0, 1 or 2;
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R h , -C(O)OR h , -C(O)NH 2 , -C(O)NHR h , -C(O)NR h 2 , -OR h , -NR h 2 , or -S(O) 2 R h ; each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR h , -NR h 2, -NR h C(O)R h , -NR h C(O)CH 2 R h , - NR h C(O)CH
• R 2 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR h , -NR h 2 , -NR h C(O)R h , -N[C(O)R h ] 2 , -NR h C(O)OR h , -NO 2 , -CN, -C(O)R h , - C(O)OR h , -C(O)NH 2 , -C(O)NHR h , -C(O)NR h 2 , -OR h , -OC(O)R h , -OC(O)OR h , -OC(O)NH 2 , -OC(O)N HR h , -OC(O)NR
• R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;
• R 21 is a bond connected to R 18 of the linker, and wherein formula (lla) and formula (lIb) each contain a single R 21 ; wherein when each is a double bond, Z is NR 2 , R 2 is hydrogen, and each R a is hydrogen, then W4 IS CR a ; wherein
• [MCL-1 ligand moiety] is a compound of Formula (A), Formula (B) or Formula (C)
• R 8 is H, R 19 , or C 1 -C 6 alkyl optionally substituted with morpholine;
• R 9 is -C(O)OH, -C(O)OC 1 -C 6 alkyl, -C(O)NH 2 , -C(O)OR 19 or-C(O)NHR 19 ,
• R 10 is -C 2-5 alkyl-O-R 13 , wherein R 13 is phenyl, naphthyl ortetraline, wherein the phenyl, naphthyl ortetraline is optionally substituted with at least one substituent selected from halogen, C 1 - C 6 alkyl and -O(C 1 -C 6 alkyl); or wherein the naphthyl is optionally substituted with -O- or -S-,
• R 11 is H, halogen or C 1 -C 6 alkyl, wherein R 20 is Me, -CH 2 -O-bromobenzaldehyde, or or when
• R 12 is and R 10 is -O-naphthyl substituted with -O- or -S-, then R 20 is , wherein indicates attachment to -O- or -S- of R 10 ; and wherein
• R 19 is a bond connected to R 14 of the linker;
• R 23 is -C(O)OH or -C(O)OC 1 -C 6 alkyl;
• Z 2 is N or C, wherein when Z 2 is N, then is a single bond; and when Z 2 is C, then is a double bond,
• R 24 is furan optionally substituted with at least one halogen, each R 25 is independently phenyl substituted with -OR 28 and optionally further substituted with at least one substituent selected from halogen and C 1 -C 6 alkyl;
• R 26 is -C(O)OR 19 or -C(O)NHR 19 ; and each R 28 is independently -C 1-3 aIkyl-( N-aIkyI piperazine) or -C 1-3 alkyl-(N-haloalkylpyrazole) and wherein each of Formula (A), Formula (B) and Formula (C) contains a single R 19 ; and wherein [linker] has the following formula
• R 14 is -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)-, -SO 2 - or is absent
• R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkyl-NH-, -cycloalkyl-NH- or is absent
• R 16 is -C 1-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH 2 -C(O)-, -CH 2 -C(O)-NH-, -CH 2 -C(O)O- or is absent
• R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x , (C 3 H 6 -O) x , or is absent x is 1-10 y is 2-10
• R 18 is -C 1-6 alkyl, heterocycloalkyl, or is absent wherein at least one of R 14 -R 18 is present.
• each alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl group is unsubstituted.
• each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR"", -NR"" 2 , - NR""C(O)R”", -NR""C(O)CH(OH)R"", -NR""C(O)OR”", -NR""SO 2 R'"', -NO 2 , -CN,-C(O)R"", -C(O)OR”", -C(O)NH 2 , -C(O)NHR”", -C(O)NR”” 2 , -OR”", -OC(O)R”", -OC(O)OR”", -OC(O)NH 2 , -OC(O)NHR”", -OC(O)NR”" 2
• R 1 is hydrogen
• R 6 is hydrogen
• Y 5 is not C- NHC(O)R"" or -C(O)OR"".
• Z 1 is NR 6 .
• [ligase ligand moiety] is of Formula (Va) and Y 5 , Y 6 and Y 7 are each CR 7 .
• Y 5 is -C-NHC(O)R""
• Y 6 is CH
• Y 7 is CH or CCI.
• L 3 is hydrogen
• Z 1 is S
• R 1 is hydrogen
• Y 7 is CH.
• the compound is of Formula (Vb) and Y 5 , Y 6 and Y 8 are each CR 7 .
• each R"" is independently alkyl, cycloalkyl, aryl or benzyl.
• Y 5 is CH;
• Y 6 is CH or CCI; and
• Yg is C-OR"" or C-NH 2 .
• Y 8 is C-OMe or C-NH 2 .
• Z is NR 2 . In other embodiments, Z is S. In some embodiments, each is a double bond.
• L is hydrogen
• one of W 1 , W 2 , W 3 and W4 is N, and the remaining three of W 1 , W 2 , W 3 and W 4 are each CR a .
• W 4 is CR a .
• two of W 1 , W 2, W 3 and W 4 is N, and the remaining two of W 1 , W 2 , W 3 and W 4 are each CR a .
• one of W 1 , W 2 , W 3 and W 4 is CR a , and the remaining three of W 1 , W 2 , W 3 and W 4 are each N.
• each R is independently hydrogen, halogen or -NR h C(O)R h .
• [ligase ligand moiety] is:
• E 1 , E 2 , E 3 and E 4 are each CR'.
• one of E 1 , E 2 , E 3 and E 4 is N and the remaining three of E 1 , E 2 , E 3 and E 4 are each CR'.
• Q 1 is CR 5 . In other embodiments, Q 2 is CR 5
• R 14 is -C 1-6 alkyl, -SO 2 - or is absent
• R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, -C 1-6 alkyl-NH-, indicates attachment to R 14 and indicates attachment to R 16 , R 16 is -C 1-6 alkyl, -C(O)-, -C(O)-NH-, -CH 2 -C(O)-NH- or is absent R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x , (C 3 H 6 -O) x , or is absent x is 1-6 y is 2-6
• R 18 is -C 1-6 alkyl, piperazine, or is absent wherein at least one of R 14 -R 18 is present.
• R 18 is -C 1-6 alkyl or is absent.
• R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, -C 1-6 alkyl-NH-, then R 14 is -C 1-6 alkyl.
• R 14 is -C 1-6 alkyl
• R 15 is piperazine, bridged piperazine, piperazine N-oxide,
• R 16 is -C(O)-, -CH 2 -C(O)-NH-, or is absent
• R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x , (C 3 H 6 -O) x , or is absent
• R 18 is -C 1-6 alkyl, wherein when R 16 and R 17 are absent, R 18 is -C 3-6 alkyl.
• R 14 is -C 2 alkyl; x is 1, 2 or 6; and y is 2.
• R 15 is piperazine, R 16 is -C(O)-, and R 17 is absent.
• R 14 is -C 2 alkyl, and R 18 is -C 1-2 alkyl.
• R 14 when R 14 is -SO 2 -, at least two of R 15 -R 18 are present, and at least one of R 15 - R 18 is not C 1-6 alkyl.
• R 14 is -SO 2 -;
• R 15 is -C 1-6 alkyl-NH-;
• R 16 is -C(O)-;
• R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x or is absent; and
• R 18 is -C 2-4 alkyl.
• R 15 is -C 2 alkyl-NH-, x is 1 or 2, y is 1 and R 18 is -C 2-4 alkyl.
• R 14 is absent; R 15 is absent; R 16 is -C(O)-NH-, or is absent; R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x , (C 3 H 6 -O) x , or is absent; a ndR 18 is -C 1-6 alkyl.
• At least one of R 14 -R 18 is not -C 1-6 alkyl.
• R 15 is -C 1-6 alkyl-NH-
• at least one of R 16 -R 18 is present.
• R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x or (C 3 H 6 -O) x
• at least one of R 14 -R 16 and R 18 is present, wherein at least one of R 14 and R 18 is not -C 1-6 alkyl.
• [linker] is selected from
• [linker] is wherein indicates attachment to [MCL-1 ligand moiety] and indicates attachment to [ligase ligand moiety].
• R 13 is
• R 8 is H, R 19 , methyl, or -CH 2 CH 2 -morpholine; R 9 is -C(O)OH or -C(O)NHR 19 ,
• R 10 is -C 3 H 6 O-R 13 wherein R 13 is tetraline, or naphthyl optionally substituted with fluorine;
• R 11 is H, Cl, F or methyl
• R 8 is R 19 or methyl; R 10 is -
• R 13 is naphthyl optionally substituted with fluorine;
• R 11 is Cl or F, and
• R 12 is
• Z 2 is C and is a double bond.
• [MCL-1 ligand moiety] is In some embodiments, the compound is:
• R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2; L 4 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(0)H, -C(O)R",- C(O)OH, -C(O)OR", -C(O)NH 2 , -C(O)NHR", -C(O)NR" 2 , -OH, -OR", -NH 2 , -NHR", -NR" 2 , -S(O) 2 H or - S(O) 2 R";
• R y is selected from wherein indicates attachment to T,
• Z 3 is O, S or NR 3 ;
• U is 0, S, NR b or CR b 2 ; each of Y 1 , Y 2 and Y 3 is independently N or CR d ; each R d is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR", -NR" 2 , -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO 2 R", -NR"SO 2 R", -NO 2 , -CN, -C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH
• each R 3 is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR", -NR" 2 , -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO 2 R", -NR"SO 2 R", -NO 2 , -CN, -C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH 2 ,
• R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2;
• L 1 is hydrogen, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, -C(O)R",-
• R x is selected from wherein indicates attachment to T,
• Z 4 is O, S or NR 4 ;
• V is CR f 2 , NR 4 or S; each of G 1 , G 2 , G 3 and G 4 is independently N or CR c , each of Y 1 and Y 2 is independently N or CR f , each R f is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, fused aryl-cycloalkyl, fused aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR", -NR" 2 , -NHC(O)R", -NR"C(O)R",
• R 4 when R x is , Z 4 is NR 4 , Y 1 is CR f , and Y 2 is N, then R 4 is not alkyl and at least one of R 2 and R is not H;
• n 1 or 2;
• [MCL-1 ligand moiety] is a compound of Formula (A), Formula (B) or Formula (C) wherein is a single bond or a double bond;
• R 8 is H, R 19 , or C 1 -C 6 alkyl optionally substituted with morpholine;
• R 9 is -C(O)OH, -C(O)OC 1 -C 6 alkyl; -C(O)NH 2 ; -C(O)OR 19 or -C(O)NHR 19 ,
• R 10 is -C 2-5 alkyl-O-R 13 , wherein R 13 is phenyl, naphthyl or tetraline, wherein the phenyl, naphthyl or tetraline is optionally substituted with at least one substituent selected from halogen, C 1 - C 6 alkyl and -O(C 1 -C 6 alkyl); or wherein the naphthyl is optionally substituted with -O- or -S-,
• R 11 is H, halogen or C 1 -C 6 alkyl
• R 20 is Me, -CH 2 -O-bromobenzaldehyde, or ;
• R 12 is and R 10 is -O-naphthyl substituted with -O- or -S-, then R 20 is , wherein indicates attachment to -O- or -S- of R 10 ; and wherein
• R 19 is a bond connected to R 14 of the linker;
• R 23 is -C(O)OH or -C(O)OC 1 -C 6 alkyl;
• Z 2 is N or C, wherein when Z 2 is N, then is a single bond; and when Z 2 is C, then is a double bond,
• R 24 is furan optionally substituted with at least one halogen
• each R 25 is independently phenyl substituted with -OR 28 and optionally further sub stituted with at least one substituent selected from halogen and C 1 -C 6 alkyl;
• R 26 is -C(O)OR 19 or -C(O)NHR 19 ; and each R 28 is independently -C 1-3 alkyl-(N-alkyl piperazine) or -C 1-3 alkyl-(N-haloalkylpyrazole) and wherein each of Formula (A), Formula (B) and Formula (C) contains a single R 19 ; and wherein [linker] has the following formula R 14 -R 15 -R 16 -R 17 -R 18 wherein
• R 14 is -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)-, -SO 2 - or is absent
• R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkyl-NH-, -cycloalkyl-N H- or is absent
• R 16 is -C 1-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH 2 -C(O)-, -CH 2 -C(O)-NH-, -CH 2 -C(O )O- or is absent
• R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x , (C 3 H 6 -O) x , or is absent x is 1-10 y is 2-10
• R 18 is -C 1-6 alkyl, heterocycloalkyl, or is absent wherein at least one of R 14 -R 18 is present
• each alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl is unsubstituted.
• Z 4 is NR 4 ; each of G 1 , G2 and G 4 is CR c , Y 1 is N, and Y 2 is CR f , wherein R f is not hydrogen.
• [ligase ligand moiety] is Formula (III):
• one of R c is -O-R 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH 2 -NH-C(O)-R 21 .
• G 1 is C-O-R 21 , C-NH-R 21 , C-C(O)-NH-R 21 , or C-CH 2 -NH-C(O)-R 21 .
• G 2 is C-O-R 21 , C-NH-R 21 , C-C(O)-NH-R 21 , or C-CH 2 -NH-C(O)-R 21 .
• R 4 is R 21 , -C(O)-NH-R 21 , or -CH 2 -NH-C(O)-R 21 .
• one of R f is - R 21 ,-O-R 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH 2 -NH-C(O)-R 21 .
• Y 2 is C-R 21 , CO-R 21 , C-NH-R 21 , C-C(O)-NH-R 21 , or C-CH 2 -NH-C(O)-R 21 .
• [ligase ligand moiety] is selected from
• [ligase ligand moiety] is of Formula (II):
• R y is selected from
• Z 3 is S or NR 3 ; U is or S; O andeach of Y 1 , Y 2 and Y 3 is independently N or CR d .
• R b is hydrogen or alkyl.
• R 3 is hydrogen, alkyl, cycloalkyl, -R 21 , -C(O)-NH-R 21 , or -CH 2 -NH-C(O)-R 21 .
• each R d is independently hydrogen, alkyl, -O-R 21 , -NH-R 21 , -C(O)-NH-R 21 , or - CH 2 -NH-C(O)-R 21 .
• R 14 is -C 1-6 alkyl, -SO 2 - or is absent
• R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, -C 1-6 alkyl-NH-, or is abse nt, wherein indicates attachment to R 14 and indicates attachment to R 16 , R 16 is -C 1-6 alkyl, -C(O)-, -C(O)-NH-, -CH 2 -C(O)-NH- or is absent R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x , (C 3 H 6 -O) x , or is absent x is 1-6 y is 2-6
• R 18 is -C 1-6 alkyl, piperazine, or is absent wherein at least one of R 14 -R 18 is present.
• R 18 is -C 1-6 alkyl or is absent.
• R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, -C 1-6 alkyl-NH-, then R 14 is -C 1-6 alkyl.
• R 14 is -C 1-6 alkyl
• R 15 is piperazine, bridged piperazine, piperazine N-oxide,
• R 16 is -C(O)-, -CH 2 -C(O)-NH-, or is absent
• R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x , (C 3 H 6 -O) x , or is absent
• R 18 is -C 1-6 alkyl. wherein when R 16 and R 17 are absent, R 18 is -C 3-6 alkyl. In some such embodiments, R 14 is -C 2 alkyl; x is 1, 2 or 6; and y is 2. In other such embodiments, R 15 is piperazine, R 16 is -C(O)-, and R 17 is - absent. In some such embodiments, R 14 is -C 2 alkyl, and R 18 is -C 1-2 alkyl. In some embodiments, when R 14 is -SO 2 -, at least two of R 15 -R 18 are present, and at least ore of R 15 - R 18 is not C 1-6 alkyl.
• R 14 is -SO 2 -;
• R 15 is -C 1-6 alkyl-NH-;
• R 16 is -C(O)-;
• R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x or is absent; and
• R 18 is -C 2-4 alkyl.
• R 15 is -C 2 alkyl-NH-; x is 1 or 2; y is 1; and R 18 is -C 2-4 alkyl
• R 14 is absent; R 15 is absent; R 16 is -C(O)-NH-, or is absent; R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x , (C 3 H 6 -O) x , or is absent; and R 18 is -C 1-6 alkyl.
• At least one of R 14 -R 18 is not -C 1-6 alkyl.
• x is 1, 2 or 3; y is 2; and R 18 is -C 2-6 alkyl.
• R 15 is -C 1-6 alkyl-NH-, at least one of R 16 -R 18 is present.
• R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x or (C 3 H 6 -O) x
• at least one of R 14 -R 16 and R 18 is present, wherein at least one of R 14 and R 18 is not -C 1-6 alkyl.
• [linker] is selected from
• R 13 is
• R 8 is H, R 19 , methyl, or -CH 2 CH 2 -morpholine; R 9 is -C(O)OH or -C(O)NHR 19 ,
• R 10 is -C 3 H 6 O-R 13 wherein R 13 is , tetraline or naphthyl optionally substituted with fluorine;
• R 11 is H, Cl, F or methyl
• R 12 is , wherein R 20 is Me, -CH 2 -O-bromobenzaldehyde, or In some such embodiments, R 8 is R 19 or methyl; R 10 is -
• R 13 is naphthyl optionally substituted with fluorine;
• R 11 is Cl or F, and
• R 12 is
• Z 2 is C and is a double bond.
• [MCL-1 ligand moiety] is In some embodiments, the compound is selected from:
• X 1 and X 2 are O. In other embodiments, X 1 is O and X 2 is S. In other embodiments, X 1 is S and X 2 is O. In other embodiments, X 1 and X 2 are S.
• n is 0. In other embodiments, n is 1 or 2. In some embodiments, n is 1. In other embodiments, n is 2.
• [MCL-1 ligand moiety] is a compound of Formula (A), and R 10 is -C 2-5 alkyl-O-R 13 ,
• R 10 is -C 3 H 6 -O-R 13 .
• a pharmaceutical composition comprising a compound according to any of the above aspects of the present invention.
• the invention also provides a compound or composition according to any of the above aspects of the present invention, for use in medicine.
• the cancer also provides a compound or composition according to any of the above aspects of the present invention, for use in the treatment of cancer.
• the cancer is selected from breast cancer, triple negative breast cancer, colorectal cancer, pancreatic cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, small-cell lung cancer, non-small- cell lung cancer, lymphoma, non-Hodgkin's lymphoma, multiple myeloma, cervical cancer, leukaemia, chronic lymphocytic leukaemia (CLL), acute myeloid leukaemia (AML), chro nic myelogenous leukemia (CML), acute lymphoblastic leukaemia (ALL), bladder cancer, and prostate cancer.
• the cancer is multiple myeloma or acute myeloid leukaemia.
• the present invention also provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or composition according to any of the above aspects of the present invention.
• the cancer is selected from breast cancer, triple negative breast cancer, colorectal cancer, pancreatic cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, small-cell lung cancer, nonsmall-cell lung cancer, lymphoma, non-Hodgkin's lymphoma, multiple myeloma, cervical cancer, leukaemia, chronic lymphocytic leukaemia (CLL), acute myeloid leukaemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukaemia (ALL), bladder cancer, and prostate cancer.
• CLL chronic lymphocytic leukaemia
• AML acute myeloid leukaemia
• CML chronic myelogenous leukemia
• ALL acute lymphoblastic leukaemia
• the cancer is multiple myeloma or acute myeloid leukaemia.
• the administration does not result in cytotoxicity in cardiomyocytes in the subject.
• the method further comprises administering at least one additional active agent to the subject.
• the at least one additional active agent is an anti-cancer agent selected from eribulin; fulvestrant; midostaurin; an immune checkpoint inhibitor selected from anti-pd-1 antibody, anti-pd-l1 antibody, and anti pd-1/pd-l1 interaction inhibitor; nivolumab; pembrolizumab; atezolizumab; pidilizumab; carfilzomib; venetoclax; cytarabine; anthracyclines; a taxane compound; and hypomethylating agents.
• an anti-cancer agent selected from eribulin; fulvestrant; midostaurin; an immune checkpoint inhibitor selected from anti-pd-1 antibody, anti-pd-l1 antibody, and anti pd-1/pd-l1 interaction inhibitor
• nivolumab pembrolizumab
• atezolizumab atezolizumab
• pidilizumab pidilizumab
• the invention also provides a compound or composition according to any of the above aspects of the present invention, for use in reversing resistance to chemotherapy or targeted cancer therapies.
• the invention also provides a method of reversing resistance to chemotherapy or targeted cancer therapies in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or composition of the present invention.
• the invention also provides a combined preparation of a compound of the present invention and at least one additional active agent, for simultaneous, separate or sequential use in therapy.
• the at least one additional active agent is an anti-cancer agent selected from eribulin; fulvestrant; midostaurin; an immune checkpoint inhibitor selected from anti-pd-1 antibody, anti- pd-l1 antibody, and anti pd-1/pd-l1 interaction inhibitor; nivolumab; pembrolizumab; atezolizumab; pidilizumab; carfilzomib; venetoclax; cytarabine; anthracyclines; a taxane compound; and hypomethylating agents.
• the therapy is the treatment of cancer.
• the invention also provides a compound of formula (X):
• the cereblon binding moiety is a [ligase ligand moiety] of the present invention.
• the MCL-1 inhibitor is an [MCL-1 binding moiety] of the present invention.
• the cereblon binding moiety is coupled to the MCL-1 inhibitor by a linker compound, wherein the linker compound is covalently attached to the cereblon binding moiety and the MCL-1 inhibitor.
• the linker compound is a [linker] of the present invention
• the invention also provides a method of reducing the cardiac cytotoxicity of an MCL-1 inhibitor, comprising coupling a cereblon binding moiety to the MCL-1 inhibitor.
• the cereblon binding moiety is a [ligase ligand moiety] of the present invention.
• the MCL-1 inhibitor is an [MCL-1 binding moiety] of the present invention.
• the cereblon binding moiety is coupled to the MCL-1 inhibitor by a linker compound, wherein the linker compound is covalently attached to the cereblon binding moiety and the MCL-1 inhibitor.
• the linker compound is a [linker] of the present invention.
• alkyl is intended to include both unsubstituted alkyl groups, and alkyl groups which are substituted by one or more additional groups.
• the alkyl group is an unsubstituted alkyl group.
• the alkyl group is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR w , -NR w 2 , -SO 2 R w , -C(O)R w , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
• the alkyl group is a C 1 -C 12 alkyl, a C 1 -C 10 alkyl, a C 1 -C 8 alkyl, a C 1 -C 6 alkyl, or a C 1 - C 4 alkyl group.
• the alkyl group is a linear alkyl group. In some embodiments the alkyl group is an unsubstituted linear alkyl group.
• the alkyl group is a linear alkyl group which is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR w , -NR w 2 , - SO 2 R w , -C(O)R w , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
• the alkyl group is a branched alkyl group.
• the alkyl group is an unsubstituted branched alkyl group.
• the alkyl group is a branched alkyl group which is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR w , -NR w 2 , -SO 2 R w , -C(O)R w , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
• alkenyl is intended to include both unsubstituted alkenyl groups, and alkenyl groups which are substituted by one or more additional groups.
• the alkenyl group is an unsubstituted alkenyl group.
• the alkenyl group is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR w , -NR w 2 , -SO 2 R w , -C(O)R w , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
• the alkenyl group is a C 2 -C 12 alkenyl, a C 2 -C 10 alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 6 alkenyl, or a C 2 -C 4 alkenyl group.
• the alkenyl group is a linear alkenyl group.
• the alkenyl group is an unsubstituted linear alkenyl group.
• the alkenyl group is a linear alkenyl group which is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR w , -NR w 2 , -SO 2 R w , -C(O)R w , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
• the alkenyl group is a branched alkenyl group.
• the alkenyl group is an unsubstituted branched alkenyl group.
• the alkenyl group is a branched alkenyl group which is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR w , -NR w 2 , -SO 2 R w , -C(O)R w , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
• alkynyl is intended to include both unsubstituted alkynyl groups, and alkynyl groups which are substituted by one or more additional groups.
• the alkynyl group is an unsubstituted alkynyl group.
• the alkynyl group is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR w , -NR w 2 , -SO 2 R w , -C(O)R w , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
• the alkynyl group is a C 2 -C 12 alkynyl, a C 2 -C 10 alkynyl, a C 2 - C 8 alkynyl, a C 2 -C 6 alkynyl, or a C 2 -C 4 alkynyl group.
• the alkynyl group is a linear alkynyl group.
• the alkynyl group is an unsubstituted linear alkynyl group.
• the alkynyl group is a linear alkynyl group which is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR w , -NR w 2 , -SO 2 R w , -C(O)R w , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
• the alkynyl group is a branched alkynyl group.
• the alkynyl group is an unsubstituted branched alkynyl group. In some embodiments the al kynyl group is a branched alkynyl group which is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR w , -NR w 2 , -SO 2 R w , -C(O)R w , -CN, and -NO 2 , wherein each R w is unsubstituted and is ind ependently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
• aryl is intended to include both unsubstituted aryl groups, and aryl groups which are substituted by one or more additional groups.
• the aryl group is an unsubstituted aryl group.
• the aryl group is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR w , -NR w 2 , -SO 2 R w , -C(O)R w , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
• the aryl group is a C 6 -C 10 aryl, a C 6 -C 8 aryl, or a C 6 aryl.
• heteroaryl is intended to include both unsubstituted heteroaryl groups, and heteroaryl groups which are substituted by one or more additional groups.
• the heteroaryl group is an unsubstituted heteroaryl group.
• the heteroaryl group is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR w , -NR w 2 , -SO 2 R w , -C(O)R w , - CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
• the heteroaryl group is a C 6 -C 10 heteroaryl, a C 6 -C 9 heteroaryl, a C 6 -C 8 heteroaryl, or a C 6 heteroaryl.
• benzyl is intended to include both unsubstituted benzyl groups, and benzyl groups which are substituted by one or more additional groups.
• the benzyl group is an unsubstituted benzyl group.
• the benzyl group is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR w , -NR w 2 , -SO 2 R w , -C(O)R w , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
• all alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl groups in the compounds are unsubstituted.
• FIG 1 is a schematic illustration of the general principle for targeted protein degradation upon treatment with a bifunctional compound.
• Bifunctional compounds of the present invention comprise an E3 ligase binding moiety (LBM) on the one end and an MCL-1 binding moiety on the other end (MBM).
• Figure 2 is an assay showing the dose-dependent effect of various compounds of the invention on the level of MCL-1 protein in the OPM-2 cell line after 6h treatment (2A) and 24h treatment (2B)
• Figure 3 is an assay showing the dose-dependent effect of compounds of the invention and reference compounds on the level of MCL-1 protein in the OPM-2 (Fig. 3A) and MV-4-11 (Fig. 3B) cell line after 3h, 6h, and 24h treatment, as indicated
• Figure 4 is an assay showing the dose-dependent effect of compound 204 of the invention on the viability of OPM-2, MV-4-11 and ARH-77 cells
• Figure 5 is an assay showing the effect of compound of the invention and the reference compound on caspase 3/7 activity in iPSC-derived cardiomyocytes (iPSC-CMs) (NB 100 mM Concentration point for AZD-5991 is not displayed because of the excessive cell death)
• iPSC-CMs iPSC-derived cardiomyocytes
• Figure 6 is an assay showing the dose-dependent effect of compounds of the invention on the population of late apoptotic/cell death (Annexin +/PI +) cells after 24 hours of treatment.
• R 14 is -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)-, -SO 2 - or is absent
• R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkyl-NH-, -cycloalkyl-NH- or is absent
• R 16 is -C 1-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH 2 -C(O)-, -CH 2 -C(O)-NH-, -CH 2 -C(O )O- or is absent
• R 17 is -CH 2 (C 2 H 4 -O) y , (C 2 H 4 -O) x , (C 3 H 6 -O) x , or is absent x is 1-10 y is 2-10
• R 18 is -C 1-6 alkyl, heterocycloalkyl, or is absent wherein at least one of R 14 -R 18 is present
• the ligase ligand moiety is: wherein
• M is O or NH, or is absent; indicates attachment to R 18 of the linker;
• R 22 is hydrogen, halogen or an amino group; and
• L' is hydrogen, alkyl, benzyl, acetyl or pivaloyl.
• A is , hydrogen, alkyl, alkenyl, benzyl, aryl, heteroaryl, haloalkyl, haloalkenyl, -CH 2 OC(O) l Bu, - CH 2 C(O)OR 27 , -C(O)R 27 , -C(O)OR 27 , -C(O)NH 2 , -C(O)NHR 27 , -C(O)NR 27 2 , -OR 27 , -NR 27 2 , -S(O) 2 R 27 or P(O)(OR 27 )(OR 27 ), wherein each R 27 is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl,
• B is hydrogen, deuterium or alkyl
• C is hydrogen, deuterium or alkyl.
• Example ligase ligand moieties of Formula (II) and Formula (III) are shown in Table 2 below.
• Compounds 4-6, 29, 39-41, 50-54, 58 and 62 could be modified to allow attachment to the [linker] (for example, by bromination of the aromatic ring followed by attachment - by palladium coupling - of either the [linker] itself, or of a functional group to which the [linker] could be attached ).
• A is , hydrogen, alkyl, alkenyl, benzyl, aryl, heteroaryl, haloalkyl, haloalkenyl, -CH 2 OC(O) t Bu, - CH 2 C(O)OR 27 , -C(O)R 27 , -C(O)OR 27 , -C(O)NH 2 , -C(O)NHR 27 , -C(O)NR 27 2 , -OR 27 , -NR 27 2 , -S(O) 2 R 27 or P(O)(OR 27 )(OR 27 ), wherein each R 27 is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl,
• B is hydrogen, deuterium or alkyl
• each D is independently deuterium or hydrogen, as shown, for example, in the compounds below:
• Example ligase ligand moieties of Formula (IV) are shown in Table 3 below.
• Compound 65 could be modified to allow attachment to the [linker] (e.g. by nucleophilic aromatic substitution; or by exchange of fluorine for bromine followed by attachment - by palladium coupling - of either the [linker] itself, or of a functional group to which the [linker] could be attached).
• Example method 1 formation of chlorinated R x group of R x COOH (or its ester R x COOR y )
• NCS (1.1 eq) was added to a solution of an appropriate starting material (1 eq) in DMF (0.5 M) and the reaction mixture was stirred for 2 h at room temperature (20-25°C). The reaction mixture was poured into water (2 x DMF volume) and occurred precipitate was filtered. The solids were washed with water and dried in vacuum to give the acid, ROOH.
• Example method 2 synthesis of R x COOH from corresponding ester R x COOR y )
• Example method 3 formation of acetylated R x group of R x COOR y
• Example ligase ligand moieties of Formula (Va) and Formula (Vb) are shown in Table 4 below. Compounds 66-74, 77-86, 88, 90-92, 96, 97 and 100 could be modified to allow attachment to the [linker] (e.g. by C-H bond activation). Table 4: 13
• Example ligase ligand moieties of Formula (lla) and Formula (lIb) are shown in Table 5 below.
• Compounds 103, 106 and 107 could be modified to allow attachment to the [linker] (e.g. by C-H bond activation).
• the moieties may be replaced with one of the following moieties: wherein
• A is , hydrogen, alkyl, alkenyl, benzyl, aryl, heteroaryl, haloalkyl, haloalkenyl, -CH 2 OC(O) t Bu, - CH 2 C(O)OR 27 , -C(O)R 27 , -C(O)OR 27 , -C(O)NH 2 , -C(O)NHR 27 , -C(O)NR 27 2 , -OR 27 , -NR 27 2 , -S(O) 2 R 27 or P(O)(OR 27 )(OR 27 ), wherein each R 27 is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl,
• B is hydrogen, deuterium or alkyl
• each D is independently deuterium or hydrogen, as shown, for example, in the compounds below:
• the [linker] has the formula R 14 -R 15 -R 16 -R 17 -R 18 wherein
• R 14 is -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)-, -SO 2 - or is absent
• R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkyl-NH-, -cycloalkyl-NH- or is absent
• R 16 is -C 1-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH 2 -C(O)-, -CH 2 -C(O)-NH-, -CH 2 -C(O)O- or is absent
• R 17 is -CH 2 (C 2 H 4 -O)y, (C 2 H 4 -O) x , (C 3 H 6 -O) x , or is absent x is 1-10 y is 2-10
• R 18 is -C 1-6 alkyl, heterocycloalkyl, or is absent wherein at least one of R 14 -R 18 is present.
• Linkers as used in the compounds of the present invention may be synthesized according to standard methods.
• linkers examples include:
• the [MCL-1 ligand moiety] is a compound of Formula (A), Formula (B) or Formula (C) as described above.
• MCL-1 ligand moieties which may be used in the compounds of the present invention include:
• linkerA-N-Boc corresponds to linkerA terminating with a Boc-protected primary or secondary amine
• linkerA-NH corresponds to linkerA terminating with a primary or secondary amine
• R5 is succinimidyl or pentafluorophenyl
• R 11 -R 13 are as defined herein; and wherein linkerA-NHC(O)-linkerB corresponds to [linker].
• This method was used for the synthesis of 201, 203, 204, 205, 206, 207, 211, 208, 210, 209, 214, 216, 213, 215, 217, 233, 241, 245, 248, 249 and 251, below.
• R 1 is -H, -C 1 -C 6 alkyl, or -NH 2 ;
• X is halogen or OMs, OTs;
• linkerA-N-Boc corresponds to linkerA terminating with a Boc-protected primary or secondary amine;
• linkerA-NH corresponds to linkerA terminating with a primary or secondary amine; and
• R 11 -R 13 are as defined herein; and wherein linkerA-N-linkerB corresponds to [linker].
• This method was used for the synthesis of 202, 233, 234, 235, 236, 237, 240 and 246, below.
• linkerA-N-R w corresponds to linkerA terminating with an R w -protected primary or secondary amine
• R 8 and R 11 -R 13 are as defined herein
• linkerA-NC(O)-linkerB corresponds to [linker].
• R 1 is -H, -C 1 -C 6 alkyl, or -NH 2 ;
• X is halogen or OMs, OTs;
• linkerA-N-Boc corresponds to linkerA terminating with a Boc-protected primary or secondary amine;
• linkerA-NH corresponds to linkerA terminating with a primary or secondary amine; and
• R 11 -R 13 are as defined herein; and wherein linkerA-N-linkerB corresponds to [linker].
• R 1 is -H, -C 1 -C 6 alkyl, or -NH 2 ;
• R 11 -R 13 are as defined herein;
• linker-N-Boc corresponds to [linker] terminating with a Boc-protected primary or secondary amine;
• linkerD-NC(O)CH 2 - corresponds to [linker] as defined herein;
• Ar is -T-R x , -T-R y ,
• R 1 is -H, -C 1 -C 6 alkyl, or -NH 2 ;
• R 11 -R 13 are as defined herein; and
• Ar is -T-R x , -T-R y ,
• the bifunctional compounds of the present invention were prepared as follows:
• Example 1 6-Chloro-3-(3-(4-chloro-3.5-dimethylphenoxy)propyl)-1-(2-(4-(3-((2-(2.6- dioxopiperidin-3-yl)-1.3-dioxoisoindolin-4-yl)amino)propyl)piperazin-1-yl)ethyl)-1H-indole-2- carboxylic acid (200)
• Step E 1-(2-(4-(3-((tert-butoxycarbonyl)amino)propyl)piperazin-1-yl)ethyl)-6-chloro-3-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid (0.01 g, 0.02 mmol) was dissolved in THF (0.08 mL) and 4M HCI in dioxane (0.02 g, 0.06 mmol) was added. Mixture was stirred for overnight in RT. Solvents were removed under reduced pressure, and crude co-evaporated three times with Et 2 O.
• Example 2 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-(4-(2-((2-(2.6- dioxopiperidin-3-yl)-1.3-dioxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-7-(1,3,5- trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (201)
• the reaction mixture was degassed and Pd(PPh 3 ) 4 (2 g, 1.7 mmol) was added under argon atmosphere.
• the reaction mixture was heated at 80°C for 24 h.
• New portion of 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (7.4 g, 31.4 mmol), K 2 CO 3 (5.5 g, 40 mmol) and Pd(PPh 3 ) 4 (4 g, 3.4 mmol) were added and the reaction was continued for 2 days. Then the solid was filtered, washed with EtOAc, and the filtrate was concentrated.
• Methyl 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)- 1H-indole-2-carboxylate (200.0 mg, 0.389 mmol) was dissolved in DMF (3.9 mL) and Cs 2 CO 3 was added followed by tert-butyl 4-(2chloroethyl)piperazine-1-carboxylate (97.7 mg, 0.393 mmol). Mixture was heated in 80°C for overnight. Solvent was evaporated, EtOAc and brine were added, and mixture was extracted with EtOAc.
• Step E 1-(2- ⁇ 4-[(Tert -butoxy)carbonyl)piperazin-1-yl ⁇ ethyl)-6-chloro-3-[3-(4-chloro-3,5- dimethylphenoxy)propyl]-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid
• 6-chloro-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-[2-(piperazin-1-yl)ethyl]-7-(1,3,5- trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid hydrochloride (38.8 mg, 0.060 mmol), was added and the mixture was allowed to stir under nitrogen for 16 h in room temperature. The reaction mixture diluted with EtOAc, washed successively with cold water (3 times) and brine. Organic layer was dried over Na 2 SO 4 and evaporated under reduced pressure.
• Example 3 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-(4-(3-((2-(2.6- dioxopiperidin-3-yl)-1.3-dioxoisoindolin-4-yl)amino)propyl)piperazin-1-yl)ethyl)-7-(1..3.5- trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (2021
• reaction mixture was purified by preparative HPLC to afford 6-chloro-3-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-1-(2-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yI)amino)propyl)piperazin-1-yl)ethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (43 mg, 0.046 mmol, 13%) as a yellow solid.
• N-hydroxysuccinimide (11.3 mg, 0.098 mmol) was added into a mixture of 1- ⁇ [2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino ⁇ -3,6,9,12,15,18- hexaoxahenicosan-21-oic acid (50.0 mg, 0.082 mmol) and DCM (1.6 mL) and the reaction mixture was kept cold at 0°C, DCC (20.3 mg, 0.098 mmol) in 0.5 mL DCM was added slowly and the mixture was stirred at room temperature for 4 hours under argon atmosphere. Solvent was removed under reduced pressure.
• Desired product was purified using flash chromatography (SiO 2 , 10% MeOH in DCM). 2,5-dioxopyrrolidin-1-yl 1- ⁇ [2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H- isoindol-4-yl]amino ⁇ -3,6,9,12,15,18-hexaoxahenicosan-21-oate (39.0 mg, 0.051 mmol, 61.9%) was obtained as yellow oil.
• Example _ 5 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-(naphthalen-1-yloxy)propyl)-7-(1,3,5-trimethyl-1H- pyrazol-4-yl)-1H-indole-2-carboxylic acid (204)
• the mixture was deoxygenated with argon and to it was added Pd(dppf)Cl 2 (1 g, 1.37 mmol) under argon atmosphere. Then the reaction mixture was heated under refl ux for 16 h. After complete consumption of the starting material (monitored by TLC and LCMS) the reaction mixture was filtered through celite pad and the solvents were evaporated under reduced pressure to get the crude material.
• Ethyl 6-chloro-3-(3-(naphthalen-1-yloxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2- carboxylate (4.2 g, 8.13 mmol) was dissolved in EtOH (100 mL) and a solution of NaOH (1.2 g, 30.0 mmol) in water (20 mL) was added to it. The mixture was heated under reflux for 3 h. The reaction mixture was cooled down to room temperature, solvents were evaporated under reduced pressure to get the crude reaction mixture. It was then diluted with water a nd washed with EtOAc.
• Example 6 6-chloro-1-(2-(4-(2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1.3-dioxoisoindolin-4- yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-(naphthalen-1-yloxy)propyl)-7-(1,3,5-trimethyl-1H - pyrazol-4-yl)-1H-indole-2-carboxylic acid (205)
• tert-butyl 6-chloro-3-(3-(naphthalen-1-yloxy)propyl)-1-(2-(piperazin- 1-yl)ethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (30.2 mg, 0.046 mmol) was added and the reaction stirred for 2 h. After that time DMF was removed, the resulting solid dissolved in EtOAc and washed 3x with water. Organic layer was collected, dried over Na 2 SO 4 , filtered and concentrated in vacuum.
• Example _ 7 6-chloro-1-(2-(4-(2-((2-(2.6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-(naphthalen-1-yloxy)propyl)-7-(1,3,5-trimethyl-1H- pyrazol-4-yl)-1H-indole-2-carboxylic acid (206)
• Step B Tert -butyl 6-chloro-1- ⁇ 2-[4-(2- ⁇ [2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4- yl]amino ⁇ acetyl)piperazin-1-yl]ethyl ⁇ -3-[3-(naphthalen-1-yloxy)propyl]-7-(1,3,5-trimethyl-1H- pyrazol-4-yl)-1H-indole-2-carboxylate (68.7 mg, crude) was dissolved in DCM (0.15mL) and then TFA (0.054 mL, 0.708 mmol) was added.
• Example 9 6-chloro-1-(2-((3 ⁇ R,6 ⁇ S)-5-(2-((2-(2.6-dioxopiperidin-3-yl)-1.3-dioxoisoindolin-4- yl)oxy)acetyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3-(3-(naphthalen-1-yloxy)propyl)- 7-(1,3.5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (211)
• Example 10 6-chloro-1-(2-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)acetyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)ethyl)-3-(3-(naphthalen-1-yloxy)propyl)-7- (1,3,5-trlmethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (208)
• Example 11 6-chloro-1-(2-(7-(2-((2-(2.6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)acetyl)-4.7-diazaspiro[2.5]octan-4-yl)ethyl)-3-(3-(naphthalen-1-yloxy)propyl)-7-(1.3.5- trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (210)
• Example 12 6-chloro-1-(2-[H5.45)-5-(2-([2-(2.6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- isoindol-4-yl]oxy ⁇ acetyl)-2.5-diazabicyclo[2.2.11heptan-2-yl]ethyl)-3-[3-(naphthalen- 1- yloxy)propyl]-7-(1.3.5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (209) Step A
• reaction mixture was diluted with DCM (25 mL) and washed with brine and water. Organic phase was combined, dried over Na 2 SO 4 , filtered and concentrated in vacuo to give crude (380.5 mg) tert-butyl (1S,4S)-5-[2-(methanesulfonyloxy)ethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as yellow oil that was used in the next step without further purification.
• Example 13 6-chloro-1-(2- ⁇ 4-[2-( ⁇ 4-[(2.6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3- benzodiazol-6-yl ⁇ oxy)acetyl]piperazin-1-yl ⁇ ethyl)-3-[3-(naphthalen-1-yloxy)propyl]-7-(1,3,5- trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (263) Step A
• Example 14 6-chloro-1-(2-(4-(2-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-methyl-1H- benzo[d]imidazol-5-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-(naphthalen-1-yloxy)propyl)-7-
• Example 15 6-chloro-1- ⁇ 2-[4-(3- ⁇ 4-[(2.6-dioxopiperidin-3-yl)carbamoyl]-1H-1.3-benzodiazol-2- yl ⁇ propanoyl)piperazin-1-yl]ethyl ⁇ -3-[3-(naphthalen-1-yloxy)propyN-7-(1,3,5-trimethyl-1H- pyrazol-4-yl)-1H-indole-2-carboxylic acid (265)
• Example 16 6-chloro-1-(2-[4- ⁇ 2- ⁇ 4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-met hyl-1H-1,3- benzodiazol-1-yl)acetyl)piperazin-1-yl]ethyl)-3-[3-(naphthalen-1-yloxy)propyl]-7-(1,3,5- trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid
• Methyl 1-(2-(tert-butoxy)-2-oxoethyl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate (30.4 mg, 0.100 mmol) was dissolved in TFA (3.0 ml) and mixed 16 h at room temperature.
• Methyl 4-hydroxy-2-(trifluoromethyl)thieno[3,4,b]pyridine-7-carboxylate (200.0 mg, 0.721 mmol) was dissolved in dry DMF (2.0 mL). To the mixture was added tert-butyl bromoacetate (0.160 mL, 1.082 mmol) and K 2 CO 3 (199.4 mg, 1.443 mmol). The reaction was stirred for 24 h at RT. The solvent was evaporated and the crude was dissolved in EtOAc and purified by flash chromatography (SiO 2 , isohaxane:EtOAc, 0-50%). Isolated fraction was concentrated in vacuo.
• Example 18 6-chloro-1- ⁇ 2-[4-(2- ⁇ [2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol- 4-yl]oxy ⁇ acetyl)piperazin-1-yl]ethyl ⁇ -3-(3-[(6-fluoronaphthalen-1-yl)oxy]propyl ⁇ -7-(1,3,5- trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (214)
• the mixture was deoxygenated with argon and to it was added Pd(dppf)Cl 2 (0.369 g, 0.505 mmol) under argon atmosphere. Then the reaction mixture was heated under reflux for 16 h. After complete consumption of the starting material (monitored by TLC and LCMS) the reaction mixture was filtered through celite pad and the solvents were evaporated under reduced pressure get the crude material.
• 6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H- indole-2-carboxylic acid (1.2 g, 2.376 mmol) was suspended in toluene (20 mL) and the mixture was heated to reflux under nitrogen.
• N.N-dimethylformamide di-tert-butyl acetal (4.547 mL, 19.01 mmol) was added drop-wise to the refluxing mixture. The mixture was heated under reflux for 16 h under nitrogen.
• Step E tert-butyl 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-chloro-3-(3-((6-fluoronaphthalen- 1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (0.3 g, 0.388 mmol) dissolved in 20 mL of 4M HCI in dioxan at 0°C and the mixture was stirred for 2 h und er nitrogen at the same temperature.
• Example 20 6-chloro-1- ⁇ 2-[4-(2- ⁇ [2-(2.6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol- 4-yl]oxy ⁇ acetyl)piperazin-1-yl]ethyll-3-[3-(5.6.7.8-tetrahydronaphthalen-1-yloxy)propyl]-7-
• the mixture was deoxygenated with argon and to it was added Pd(dppf)Cl 2 (1.12 g, 1.5 mmol) under argon atmosphere. Then the reaction mixture was heated under reflux for 16 h. After complete consumption of the starting material, the reaction mixture was filtered through celite pad and the solvents were evaporated under reduced pressure get the crude material.
• Ethyl 6-chloro-3-(3-((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H- pyrazol-4-yl)-1H-indole-2-carboxylate (4.0 g, 7.7 mmol) was dissolved in EtOH (50 mL) and a solution of NaOH (1.5 g, 38.5 mmol) in water (40 mL) was added to it. The mixture was heated under reflux for 16 h. After complete consumption of the starting material, the reaction mixture was cooled down to room temperature, solvents were evaporated under reduced pressure to get the crude reaction mixture. It was then diluted with water, washed with EtOAc.
• 6-chloro-7-(3,5-dimethyl-1H-pyrazol-4-yl)-3-(3-((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)propyl)- 1H-indole-2-carboxylic acid (3.3 g, 6.9 mmol) was suspended in toluene (50 ml) and the mixture was heated to reflux under nitrogen.
• N,N-dimethylformamide di-tert-butyl acetal (12 ml, 53.7 mmol) was added drop wise to the refluxing mixture. The mixture was heated under reflux for 16 h under nitrogen.
• reaction mixture was then diluted with EtOAc, washed successively with aqueous NaHCO 3 (sat.), water and brine, organic layer was dried over Na 2 SO 4 and evaporated under reduced pressure to get the crude compound, which was then purified by flash chromatography (SiO 2 , 70% EtOAc in hexane) to get 3.3 g (6.0 mmol, 87%) of tert-butyl 6-chloro-3-(3-((5,6,7,8-tetrahydronaphthalen-1- yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate as brown solid.
• Step F Tert-butyl 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-chloro-3-(3-((5,6,7,8- tetrahydronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2- carboxylate (3.0 g, 3.95 mmol) was dissolved in 50 mL of 4M HCI in dioxane at 0°C and the mixture stirred for 2 h under nitrogen at same temperature. The reaction mixture was poured in to cold 1M NaOH solution and extracted several times with DCM.
• Reaction mixture was then allowed to cool down to RT and a solution of tert-butyl 6-chloro-1-[2-(piperazin-1-yl)ethyl]-3-[3-(5, 6,7,8- tetrahydronaphthalen-1-yloxy)propyl]-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2- carboxylate (50.0 mg, 0.076 mmol) and DIPEA (0.040 mL, 0.227 mmol) was added in 1 ml of DMF. The reaction was stirred in RT for 72 h.
• Example 21 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-((2-(3-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanamido)ethyl)sulfonyl)-1-methyl-7-(1.3.5-trimethyl-1H-pyrazol-
• Step B lodomethane (0.133 mL, 2.138 mmol) was added to a stirred mixture of methyl 6-chloro-3-(3-(4- chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (1.000 g, 1.944 mmol) in DMF (6.0 mL), followed by K 2 CO 3 (0.672 g, 4.860 mmol). The resulting mixture was stirred at room temperature for 24 hours. After the reaction was completed solvents were evaporated and the resulting residue was partitioned between EtOAc and H 2 O.
• Example 22 1- ⁇ 2-[4-(2- ⁇ [2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4- yl]oxy)acetyl)piperazin-1-yl]ethyl)-6-fluoro-3-[3-(naphthalen-1-yloxy)propyl]-7-(1,3,5- trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (213)
• the mixture was deoxygenated with argon and to it was added Pd(dppf)Cl 2 (0.629 g, 0.86 mmol) under argon atmosphere. Then the reaction mixture was heated under reflux for 16 h. After complete consumption of the starting material the reaction mixture was filtered over celite and the filtrate was evaporated under reduced pressure to get the crude material.
• Example 23 1- ⁇ 2-[4-(2- ⁇ [2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4- yl]oxy ⁇ acetyl)piperazin-1-yl]ethyl ⁇ -6-fluoro-3-(3-[(6-fluoronaphthalen-1-yl)oxy]propyl ⁇ -7- (1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (215)
• reaction product was purified by preparative HPLC (lOmM ammonium acetate in H 2 O:MeCN) to get of tert- butyl 6-fluoro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1-(2-(piperazin-1-yl)ethyl)-7-(1,3,5- trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (225 mg, 0.34 mmol, 28 %) as off white solid.
• Reaction product was washed from silica gel with eluent solution, filtered and dried under reduced pressure to give 1- ⁇ 2-[4-(2- ⁇ [2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4- yl]oxy ⁇ acetyl)piperazin-1-yl]ethyl ⁇ -6-fluoro-3- ⁇ 3-[(6-fluoronaphthalen-1-yl)oxy]propyl ⁇ -7-(1,3,5- trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (3.1 mg, 0.003 mmol, 6% yield over two steps) as off white solid.
• Example _ 24 _ 1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)acetyl)piperazin-1-yl)ethyl)-6-methyl-3-(3-(naphthalen-1-yloxy)propyl)-7-(1,3,5- trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (217)
• the mixture was deoxygenated with argon and to it was added Pd(OAc) 2 (0.124 g, 0.552 mmol) under argon atmosphere. Then the reaction mixture was heated under reflux for 16 h. After complete consumption of the starting material (monitored by TLC and LCMS) the reaction mixture was filtered through celite pad and the solvents were evaporated under reduced pressure. It was then diluted with EtOAc and washed successively with water and brine.
• Step B To a well stirred solution of tert-butyl 6-methyl-3-(3-(naphthalen-1-yloxy)propyl)-7-(1,3,5- trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (1.6 g, 3.05 mmol) in DMF (15 mL) was added tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (1.5 g, 6.119 mmol) followed by cesium carbonate (4.9 g, 15.296 mmol) in DMF and the mixture was allowed to stir at 90°C for 16 h under nitrogen.
• Example 25 3-(3-(4-chloro-3.5-dimethylphenoxy)propyl)-7-(1-(3-(2-(2-((2-(2.6-dioxopiperidin- 3-yl)-1.3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propyl)-3.5-dimethyl-1H-pyrazol -4-yl)-1- methyl-1H-indole-2-carboxylic acid (227)
• Step G To a stirred solution of ethyl 7-bromo-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-methyl-1H- indole-2-carboxylate (5 g, 10.46 mmol) in dioxane (150 mL) and water (30 mL) were added 3,5- dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (7 g, 31.4 mmol) and K 2 CO 3 (5.8 g, 41.84 mmol).
• the mixture was deoxyge rated with argon and to it was added Pd(dppf)CI 2 (1.14 g, 1.57 mmol) under argon atmosphere. Then the reaction mixture was heated under reflux for 16 h. After complete consumption of the starting material the reaction mixture was filtered through celite pad and the solvents were evaporated under reduced pressure get the crude material.

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